How VE-PTP and Tie-2 regulate endothelial cell junctions in VE-cadherin dependent and independent ways

VE-PTP和Tie-2如何以VE-钙粘蛋白依赖和独立的方式调节内皮细胞连接

• 批准号: 427774878
• 负责人: Professor Dr. Dietmar Vestweber
• 金额: --
• 依托单位: Max-Planck-Institut für molekulare Biomedizin
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/427774878?language=en
• 关键词: How; VE; PTP; Tie; regulate

The endothelial specific Vascular Endothelial Protein Tyrosine Phosphatase (VE-PTP) is a receptor type tyrosine phosphatase (R-PTP) which is a major regulator of endothelial junctions, vascular permeability and leukocyte extravasation. We have shown that this phosphatase associates with and regulates the function of VE-cadherin, an adhesion molecule, which is of central importance for the integrity of endothelial junctions. In addition, we found that VE-PTP regulates the activity of the tyrosine kinase receptor Tie-2, which stabilizes junctions. Consequently, VE-PTP is a valuable pharmacological target for the stabilization of endothelial junctions and for the inhibition of inflammation induced vascular leak formation. Indeed, the highly specific inhibitor of VE-PTP, AKB9778, is able to protect from leak formation in inflammation models in the mouse and is presently tested successfully in phase II trials on diabetic retinopathy in patients. The purpose of this proposal is to elucidate the detailed mechanisms by which the inhibition of VE-PTP supports vascular integrity. We will analyze how the effects of VE-PTP on Tie-2 and VE-cadherin relate to each other and which other substrates and signaling targets of VE-PTP are involved in the regulation of endothelial junctions.

内皮特异性血管内皮蛋白酪氨酸磷酸酶（VE-PTP）是一种受体型酪氨酸磷酸酶（R-PTP），是内皮连接、血管通透性和白细胞外渗的主要调节因子。我们已经表明，这种磷酸酶与VE-钙粘蛋白，一种粘附分子，这是至关重要的内皮连接的完整性，并调节其功能。此外，我们发现VE-PTP调节酪氨酸激酶受体Tie-2的活性，从而稳定连接。因此，VE-PTP是稳定内皮连接和抑制炎症诱导的血管渗漏形成的有价值的药理学靶标。事实上，VE-PTP的高度特异性抑制剂AKB 9778能够防止小鼠炎症模型中的渗漏形成，目前已在糖尿病视网膜病变患者的II期试验中成功测试。本提案的目的是阐明VE-PTP抑制支持血管完整性的详细机制。我们将分析VE-PTP对Tie-2和VE-cadherin的影响如何相互关联，以及VE-PTP的其他底物和信号靶标参与内皮连接的调节。